Interest: Alcohol as neurotoxicant and neuroprotectant
One of the laboratory interests is mechanisms of brain neurodegeneration and
neuroprotection relevant to alcohol. Our studies with adult rats have clarified
that subchronic, repetitive alcohol intoxication sufficient to achieve the high
blood levels occurring in binging alcoholics causes brain edema as well as selective
neuronal necrosis in the hippocampus, limbic cortex and olfactory glomeruli.
The fact that diuretic agents which prevent brain edema are neuroprotective whereas
antagonists to glutamate receptors, Ca++ channels, and nitric oxide formation
are not suggests that nonsynaptic brain hydration is more involved than synaptic
excitotoxicity. Organotypic rat brain hippocampal- cortical slice cultures are
being employed to further study mechanisms. In these cultures, neuroprotection
with phospholipase A2 inhibitors and antioxidants indicate that episodic alcohol
exposure may induce damaging oxidative stress in part by mobilizing arachidonic
acid, but cell swelling appears to be an essential early event, because diuretics
including several lacking antioxidant potential are still neuroprotective. With
the slice cultures we are also examining alcohol's interactions with other neurotoxic
agents-in particular, HIV-1 envelope protein gp120, which may underlie brain
damage in AIDS. The studies may contribute to the limited knowledge of the CNS
effects of social and abusive drinking during AIDS. Experiments show that alcohol
in high neurotoxic concentrations augments HIV-1 gp120-induced neurodegeneration,
but low/moderate alcohol concentrations, either in a pretreatment or cotreatment
protocol, are neuroprotective. Moderate alcohol appears to selectively impair
the ability of the retroviral protein to mount glial-dependent excitotoxic cascades
mediated by increased glutamate, arachidonic acid, and oxygen free radicals.
The molecular mechanisms underlying this alcohol effect are under study.
